Chronic Acidosis Rewires Cancer Cell Metabolism Through PPARα Signaling

The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Using cancer cells adapted to growth at extracellular pH (pHe) 6.5, we show that the acid adaptation-induced phenotype is characterized by increased metabolic flexibility, mitochondrial hyperfusion, increased peroxisome- and lipid droplet content, elevated triacylglycerols, and fatty acid desaturation. Acid adapted cells increase net acid-extruder expression yet cytosolic pH (pHi) remains acidic at pHe 6.5, becoming alkaline only at pHe values simulating conditions outside the tumor core. Acid adaptation-upregulated genes and proteins are dominated by peroxisome proliferator-activated receptor-α (PPARA, PPARα) and its targets, including peroxisomal biogenesis factor-11 and carnitine palmitoyltransferases - supporting peroxisomal and mitochondrial lipid metabolism - and the metabolic regulator thioredoxin-interacting protein (TXNIP). PPARα inhibition abolishes TXNIP upregulation, and TXNIP knockdown partially prevents acid adaptation-induced downstream events. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.